ArticleJournal of the American Chemical Society2016
A Single Aspartate Coordinates Two Catalytic Steps in Hedgehog Autoprocessing.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Site-Specific Abiraterone Protein-Drug Conjugates via Hedgehog Autoprocessing.ACS applied materials & interfaces · 2026Article
- In vitro reconstitution of vertebrate Sonic Hedgehog protein cholesterolysis.bioRxiv : the preprint server for biology · 2026Article
- Conserved C143 forms a branched intermediate in Hedgehog autoprocessing: A cancer drug discovery target against Hedgehog signaling.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Paracatalytic induction: Subverting specificity in hedgehog protein autoprocessing with small molecules.Methods in enzymology · 2023Article
- Hedgehog Autoprocessing: From Structural Mechanisms to Drug Discovery.Frontiers in molecular biosciences · 2022Review
- Hedgehog proteins create a dynamic cholesterol interface.PloS one · 2021Article
- Intein Inhibitors as Novel Antimicrobials: Protein Splicing in Human Pathogens, Screening Methods, and Off-Target Considerations.Frontiers in molecular biosciences · 2021Review
- Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.Biochemistry · 2020Article
- Methods to Study the Structure and Catalytic Activity of cis-Splicing Inteins.Methods in molecular biology (Clifton, N.J.) · 2020Article
- General Base Swap Preserves Activity and Expands Substrate Tolerance in Hedgehog Autoprocessing.Journal of the American Chemical Society · 2019Article
- Sterol A-ring plasticity in hedgehog protein cholesterolysis supports a primitive substrate selectivity mechanism.Chemical communications (Cambridge, England) · 2019Article
- Genetically Encoded Cholesterol-Modified Polypeptides.Journal of the American Chemical Society · 2019Article
- Chemical Bypass of General Base Catalysis in Hedgehog Protein Cholesterolysis Using a Hyper-Nucleophilic Substrate.Journal of the American Chemical Society · 2018Article
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Authors and funding
5 authors.
Funding
Abstract
Hedgehog (Hh) signaling is driven by the cholesterol-modified Hh ligand, generated by autoprocessing of Hh precursor protein. Two steps in Hh autoprocessing, N-S acyl shift and transesterification, must be coupled for efficient Hh cholesteroylation and downstream signal transduction. In the present study, we show that a conserved aspartate residue, D46 of the Hh autoprocessing domain, coordinates these two catalytic steps. Mutagenesis demonstrated that D46 suppresses non-native Hh precursor autoprocessing and is indispensable for transesterification with cholesterol. NMR measurements indicated that D46 has a pKa of 5.6, ∼2 units above the expected pKa of aspartate, due to a hydrogen-bond between protonated D46 and a catalytic cysteine residue. However, the deprotonated form of D46 side chain is also essential, because a D46N mutation cannot mediate cholesteroylation. On the basis of these data, we propose that the proton shuttling of D46 side chain mechanistically couples the two steps of Hh cholesteroylation.
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Registered trials
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